The present invention relates to compositions and methods for treating, reducing, ameliorating, or preventing infections. In particular, the present invention relates to such compositions comprising a quinolone carboxylic acid or a derivative thereof, and an additional anti-infective medicament; and to methods of using such compositions. More particularly, the present invention relates to such compositions comprising a fluoroquinolone carboxylic acid or a derivative thereof, and an additional anti-infective medicament; and to methods of using such compositions.
Pathogens continue to pose a serious threat to public health as indicated by a worldwide resurgence of diseases caused by bacteria, fungi, and/or viruses. Infections by pathogenic microorganisms affect a large number of patients every year. Common infections include those of the ear, respiratory system, and eye. An experienced medical practitioner often can determine the etiology of an infection and, therefore, prescribe an effective treatment. However, infections are often caused by mixed types of microorganisms that may not be immediately obvious on presentation. Consequently, an initial treatment regimen may not be immediately effective and must be replaced with another. In cases where the patients are especially vulnerable, such as those with a compromised immune system, a delayed onset of a beneficial effect of the treatment may lead to increased risk of more serious complications.
Otitis media, an infection of the middle ear, is a major worldwide infection in children. By the age of 2 years, seventy percent of children have experienced at least one episode of acute otitis media (“AOM”). T. Heikkinen et al., Clin. Microbiol. Rev., Vol. 16, No. 2, 230 (2003). Otitis media can also occur in adults. AOM is generally considered a bacterial infection that is treated with antibiotics. The three most common bacteria isolated from the middle ear fluid (“MEF”) are Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. See; e.g., J. T. Kirchener, American Family Physician, Apr. 15, 1999. However, since the 1980s, viruses have also been detected in the MEF of children with AOM in approximately twenty percent of the cases. T. Heikkinen et al., supra. The common respiratory viruses such as human rhinovirus, respiratory syncytial virus, influenza viruses, and coronavirus, have been found in children MEF. In addition, in a recent study, fungal DNA was detected in MEF of some patients with recurrent AOM and serous otitis media.
In cases of otitis externa, an infection of the external ear canal, mixed bacteria and fungi have often been found. Pseudomonas aeruginosa and Staphylococcus aureus are the most common bacteria species, and Aspergillus and Candida fungus species account for over ninety percent of the cases in which fungi are present. However, fungus is occasionally the primary pathogen in otitis externa, especially in the presence of moisture and heat. R. Sander, American Family Physician, Vol. 63, No. 5, 927 (2001).
Infections of the upper respiratory system are also common. The common cold is mostly of viral etiology. However, bacteria and fungi have also often caused other infections of the upper respiratory system. Bacteria are the most common infectious agents in sinusitis. Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis have been found in most of cases of sinusitis. Other possible bacterial culprits include other streptococcal strains and Staphylococcus aureus. While fungi are an uncommon cause of sinusitis, the incidence of such infections is increasing. The most common fungi involved in sinusitis are Asperillus species; in particular, Asperillus fumigatus. Other fungi that can cause sinusitis include Curvularia (in particular, Curvularia lunata), Bipolaris, Exserohilum, and Mucomycosis. See, Sinusitis, at http://adam.about.com (visited on Feb. 20, 2007). While fungal sinusitis is mostly non-invasive and does not lead to serious complications, rare cases of invasive fungal sinusitis caused by the fungus Scopulariopsis acremonium have been reported. Invasive fungal sinusitis is potentially fatal for immunocompromised patients. M. D. Ellison et al., Arch. Otolaryngol. Head Neck Surg., Vol. 124, 1014 (1998). It can lead to tissue invasion and destruction of adjacent structures (e.g., orbit, central nervous system). Therefore, early detection and treatment are vital for these patients.
Keratitis and conjunctivitis, two common ocular infections, are caused mostly by bacteria, fungi, and/or viruses. Numerous cocci (Staphylococcus, Streptococcus, and Neisseria species) and bacilli (Corynebacterium, Propionobacterium, Clostridium, Pseudomonas, Klebsiella, Hemophilus, Moraxella, Proteus, Serratia, Escherichia, and Enterobacter species) have been isolated from cases of ocular infections. Among the fungi causing ocular infections are Aspergillus, Fusarium, and Candida species. Herpes simplex virus (“HSV”), Varicella zoster virus, Andenovirus, and Molluscum contagiosum have been found in cases of viral ocular infections. See; e.g., G. M. Bohigian and Shailaja Valluri, in Handbook of Ocular Infections, Inflammation, and External Diseases, Chapter 2. Moreover, several studies have identified mixed microorganism types in ocular infections, such as mixtures of bacteria and HSV, bacteria and Andenovirus, or bacteria and fungi. See; e.g., M. J. Bharathi et al., Br. J. Ophthalmol., 90, 1271 (2006); S. K. Basak, Indian J. Ophthalmol., Vol. 53, No. 1, 17 (2005).
An additional challenge in the treatment of infections is the emergence of bacterial resistance to antibiotics. Such resistance may be attributed to prior widespread, and largely effective, therapeutic and prophylactic use of antibiotics, which, unfortunately, over time has also selected for resistant strains of various bacterial pathogens. Of particular concern to the public health have been the emergence and proliferation of bacterial strains that are resistant to multiple antibiotics in the current arsenal of antimicrobial agents. Therefore, a condition may not respond to an initially prescribed therapy, and, in such a case, another medicament must be given, resulting in delayed control of the pathogen.
Therefore, there is a continued need to develop improved pharmaceutical compositions that can begin to provide benefits to patients in combating infections that do not have clear etiology, soon after being administered to the patients. It is also very desirable to provide pharmaceutical compositions that minimize the risk of complications of the primary infection due to the delayed onset of effectiveness of the treatment.